This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the proposed research is to develop and use models of modest excitotoxic hippocampal injury to assess the cognitive enhancing ability of specific candidate compounds. Our preliminary data demonstrate that excitotoxic injury to the dorsal hippocampus produces enduring deficits in spatial working memory. We have also shown in preliminary studies that antagonists at histamine H3 receptors alleviate injury-induced deficits in spatial working memory. The specific aims of our currently-funded R15 research have been to answer the following questions: 1) Can H3 antagonists alleviate spatial working memory deficits in rats with adult-onset hippocampal injury, 2) Can direct infusion of H3 antagonists into the prefrontal cortex improve memory in rats with adult-onset hippocampal injury, &3) Can H3 antagonists alleviate changes in spatial working memory, prepulse inhibition, and locomotor activity in rats with neonatal-onset hippocampal injury? For this application, we requested INBRE supplemental support for a research associate who can advance the aims of our R15 research and supervise undergraduate research. Between May 2009 and the present, we have assessed the effects of H3 antagonists on spatial memory deficits and other behavioral anomalies produced by drugs that block NMDA receptors. These studies, mainly performed by Molly Griffith, our research associate, and several undergraduates in the lab, have shown that H3 antagonists exacerbate the effects of NMDA antagonists on locomotor activity, but also alleviate the spatial memory deficits produced by such drugs. We submitted an R15 to continue these studies in June 2009 and it received a priority score of 37. We will revise and resubmit this application in February 2010. Having INBRE support for our research associate has greatly facilitated the pace of our R15 research and resulted in two published papers, support for award-winning undergraduate research, and an R15 renewal application that received a favorable (although unfundable) score.